This proposal is for the continuation from the fourteenth through eighteenth years of investigations of aging associated alterations of immune function by investigators in the Immunology Department of The Scripps Research Institute. Over the years, research supported by this grant has played a major role in moving the understanding of the impact of aging on immune responsiveness from purely phenomenological observations at the level of the whole organism, through quantitative and qualitative examinations of alterations in T cell and B cell at the population level, to the initial stages of delineating the underlying alterations in subcellular enzymatic and molecular processes. In its current iteration this program project represents the integrated efforts of three laboratories investigating aging associated alterations in defined B and T cell subpopulations at the cellular, subcellular, and molecular levels. Dr. Linton (Project II) will capitalize on the identification of a distinct "aging phenotype" in the sequences of phosphorylcholine specific antibodies to compare alterations in defined B cell subsets including her recently defined precursor subset that is responsible for the generation of memory B cells and germinal centers. She will also study the tolerance susceptibility of these cells in mice expressing the influenza hemagglutinin as a transgene. Her studies of the aging associated defect in memory B cell generation will, include a collaboration with Dr. Weigle (Project III) to analyze the competence of TH subsets from young vs aged conventional mice, and (with Dr. Susan Swain) mice expressing a cytochrome c specific TCR as a transgene. Dr. Linton will also provide defined precursor subsets to Dr. Klinman (Project I) who has identified fundamental aging associated change in H chain V region rearrangement that underlie alterations in repertoire expression including those responsible for the "aging phenotype" of PC responsive B cells. Dr. Klinman will further elucidate the generality and mechanism of this aging associated alteration in gene rearrangement and will evaluate the pace of alterations of precursor cell subsets in various murine strains and possibly humans as well. Dr. Weigle will continue to pursue his seminal studies of the molecular basis of aging associated changes in the function, antigenic stimulation, and tolerance induction of CD4 + T cell subsets. He will assess the pace of these changes in conventional and, autoimmune murine strains as well as diet restricted mice. These sets of mice will also be studied for changes in B cell responses in Projects I and II.